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152 Cards in this Set
- Front
- Back
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Hemostasis:
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physiological healthy mechanism to stop bloodloss and keep it liquid.
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Thrombosis:
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pathological formation of bloodclots
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Hemorrhage:
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pathological bleeding and inability to form blood clots
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8 components of hemostasis:
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-Vascular wall
-Vascular endothelium -Platelets -Fibrinogen -Clotting factors -Calcium -Fibrinolytic enzymes -Regulatory factors |
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Components of primary hemostasis:
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-Platelets
-Vasoconstriction |
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Components of secondary hemostasis:
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-Clotting factors
-Fibrin |
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3 Main Processes that occur during primary hemostasis:
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platelet
-Adhesion -Activation -Aggregation |
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Why the vasoconstriction in primary hemostasis?
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To minimize bloodloss at penetrating injury sites.
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Purpose of secondary hemostasis:
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Fibrin formation to stabilize the platelet clot
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Which stage takes longer?
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Secondary
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What is wound healing?
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The process of clot remodeling and removal in the days and weeks following injury.
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3 Processes involved in wound healing:
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-Fibrinolysis
-Angiogenesis -Tissue remodeling |
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Where are platelets produced?
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-Bone marrow
-Spleen |
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What are platelets produced from?
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Polyploid progenitor megakaryocyte
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How are platelets born?
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By megakaryocyte fragmentation
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What does polyploid mean?
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64N
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Platelet structure features:
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-No nucleus
-Actin contractile elements -Large surface area -Organelles |
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3 types of granules in platelets:
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-Alpha
-Dense -Lysosomes |
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What 5 proteins are stored in platelet alpha granules?
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-vWF
-factor V -Fibrinogen -P-selectin -PDGf |
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What do platelets biosynthesize?
From what? |
TxA2 from Arachidonic acid
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What are 3 stored metabolites in dense granules?
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-ADP
-Calcium -Serotonin |
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When do platelets release their granules?
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When activated
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4 things that platelets have receptors for:
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1. Adhesion
2. Thrombin 3. ADP 4. TxA2 |
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What is the plt receptor for fibrinogen?
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GPIIb-IIIa
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What is required for the plt fibrinogen receptor to be active?
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Activation by the binding of Thrombin, ADP, or TxA2
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How do platelets activate to adhere?
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By spreading out by their actin filaments
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What allows platelets to detect the appropriate site for adherence during primary clotting?
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vWF - found on the collagen of the vascular wall underlying the endothelium
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What is the platelet receptor for vWF factor?
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GP1b-a
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How does vWF get onto the vascular wall?
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Circulating vWF binds to it; this ccauses a conformational change so it can interact with its platelet receptor.
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What happens to platelets when they bind vWF via their GPIb-a receptor?
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They undergo shape change (actin) and release stored mediators in their granules.
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What is the result of platelets releasing stored mediators like ADP?
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Attraction and activation of more platelets.
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2 most important mediators for aggregation released by activated / shape-changed platelets on injury site:
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-ADP
-TxA2 |
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What happens when platelets release ADP and TxA2?
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It calls additional platelets to adhere to the initial clot.
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What happens after platelets are adhered, activated, and aggregated?
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Their Fibrinogen GPIIbIIIa receptor has been activated so it can bind to fibrinogen swimming in the blood.
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What is achieved by fibrinogen binding?
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It links together many MORE platelets (glue) and leads to aggregation - achieves formation of primary platelet clot.
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How stable is the primary clot?
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Not very stable
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How is the clot stabilized?
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By activation of the coagulation cascade - the endproduct being Thrombin which modifies the crosslinking of platelets by converting fibrinogen to fibrin.
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What exactly does Thrombin do to soluble Fibrinogen?
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Cleaves 2 AA from its N-terminal
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What is the result of cleaving fibrinopeptides A/B from Fibrinogen monomer?
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It generates sticky fibrin monomers that spontaneously POLYMERIZE to generate a huge aggregate - stabilizes clot.
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What molecule is essential for crosslinking of fibrinogen polymers?
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Factor 13
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What exactly is the function of factor 13?
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Irreversible crosslinking of fibrin polymers by covalently binding them together.
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How do you know there is enough fibrinogen available for clotting?
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It is the most abundant protein in plasma after albumin.
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What activates factor 13?
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Thrombin (same thing that converts fibrinogen into fibrin monomers).
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What disease is associated with lack of GPIIb-IIIa? What is this receptor again?
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Glanzmann's thrombasthenia - this is the fibrinogen receptor.
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What is the GP1b-a receptor? What disease is associated with it?
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vWF-receptor; mutation causes Bernard Soulier syndrome
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What mutation causes von Willebrand disease?
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vWF mutation
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Where are coag factors found? In what state?
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Circulating in blood as inactive proenzymes
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What is essential for coag factors to function?
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Activation by enzymatic proteases
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What is the endproduct of the coag cascade?
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Activation of Prothrombin into Thrombin.
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2 Main functions of Thrombin:
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-Cleaves fibrinogen into fibrin
-Activates Platelets |
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Where are most coag factors made?
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In the liver
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Exceptions to liver synthesis:
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-Factor V (liver/megakaryos)
-vWF (endothelium/megakaryos) -Tissue factor (not endothelium) |
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What are the vit K dependent factors?
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2,7,9,10, Proteins S and C
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Which coag factors are cofactors?
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5, 8, Ca, Phospholipid, TF, and Protein S
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Which coag factors are the most abundant and highest in concentration?
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-Fibrinogen
-Thrombin |
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Which coag factor acts as a chaperon for Fx VIII?
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vWF!
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How are vit K dependent and independent coag factors different?
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Based on the AA sequence that consists of their active site.
But they look structurally similar. |
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What is the reactive site used by VitK dependent factors?
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AGY
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What is the reactive site used by VitK independent factors?
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TCN
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What is VitK dependence?
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Posttranslational carboxylation and addition of glutamic acids to the Gla of VitK dependent Fxs
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What is the result of carboxylation of glutamic acid residues of Vit K dependent coag factors?
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They become sensitive to calcium.
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Where is the source/function of calcium here?
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Released locally from activated platelets - allows the factors to assemble into little machines to generate thrombin.
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What blocks the vit-K dependent carboxylation of the factors?
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Warfarin
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What is necessary for coag factors to be active? What does activation result in?
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Limited proteolysis; results in release of the business end Catalytic Serin Protease domain.
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what initiates the coagulation reactions (extr/intr)?
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Extrinsic: tissue factor/VII
Intrinsic: surface type in vitro |
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What processes happen after initiation of the coag reaction?
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-Amplification mediated by platelets and thromin
-Termination via an endogenous anticoagulant mechanism. |
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What is the purpose of terminating the coagulation reaction?
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To limit the clot to the site of injury.
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Why is the intrinsic pathway called that?
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Intrinsic mechanism of clotting - platelets will just clot when contacting a surface.
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What are TENase and PROTHROMBINase?
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The 2 important 'machines' in the common pathway that generate massive amts of thrombin.
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What does TENase consist of?
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-9a/8a
-platelet cofactors -calcium |
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What does Prothrombinase consist of?
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-Xa/Va
-platelet cofactors -calcium |
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What initiates coagulation?
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Tissue Factor
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Where is Tissue factor? How does it activate coagulation?
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Membrane bound on muscles - sticks out and when injured binds and activates Fx VII
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What does Fx 7a do?
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-Activates Fx 9
-Activates Fx 10 |
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What does factor Xa do?
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Activates a LITTLE BIT of thrombin from prothrombin - not by the action of machines.
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What happens after Xa is made and what makes it happen?
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Propagation and amplification - done by Thrombin itself - the little bit initially formed.
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What is involved in propagation and amplification?
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Thrombin activates the other cofactors to assemble the enzyme machines Tenase and Prothrombinase - these make LOTS of thrombin.
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What type of feedback allows propagation and amplification?
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Positive
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4 Mechanisms by which the coagulation reaction is LIMITED:
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1. Localization of enzyme generation
2. Specific destruction of cofactors/activated cofactors 3. Plasma protease inhibitors 4. Bloodflow |
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How does enzyme generation localization help limit coagulation?
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Because assembly of the enzyme machines occurs only at sites of injury via interaction w/ platelets - floating molecules are less active.
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What molecules achieve specific destruction of factors and cofactors to limit coagulation?
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-Thrombomodulin
-Protein C |
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What are 2 ways by which normal non-injured endothelial cells limit and stop coagulation?
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1. By inhibiting plt activation
2. By inhibiting coagulation activation |
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3 inhibitors of platelet activation produced by normal non-injured endothelial cells:
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-Nitric oxide
-Ecto-ADPase -Prostaglandin I2 |
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What are the plasma protease inhibitors? (3)
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1. AT III / Heparin
2. Heparin cofactor II 3. Tissue Factor Pathway inhibitor |
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How does bloodflow limit coagulation?
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-Removes/dilutes activated factors
-Hepatic clearance |
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What is the essential requirement for AT3 to work?
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NORMAL Endothelium - it has HEPARANSULPHAT proteins with LOTS of sugar residues attached
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What is the function of the proteoglycans on endothelium in the AT3 mechanism?
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Sugars lure in Thrombin and change its conformation when it binds so that Thrombin then lures in Antithrombin.
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How does AT3 behave when lured in by Thrombin bound to heparansulphat?
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As a suicide bomber; binding Thrombin forms an irreversible TAT complex and molecular destruction ensues.
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What does AT3 do after forming the TAT complex with thrombin?
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AT3 turns thrombin inside out.
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How is it that AT3 which is constantly present in the blood, doesn't inhibit clotting and thrombin constantly?
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It requires the polysaccharides on normal endothelium; if it's damaged, it won't inhibit it.
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How do heparan-like drugs work?
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By facilitating the formation of TAT complexes in hypercoagulable states - inhibit coagulation.
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What is thrombomodulin?
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A molecule that modulates Thrombin; bound to normal uninjured endothelium
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What is thrombomodulin situated next to on the endothelial membrane?
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Protein C receptor
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What binds the Protein C receptor?
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Protein C - it is Vit K dependent and always circulating and bound to uninjured endothelium, but inactive.
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How does Thrombomodulin function?
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1. Thrombomodulin binds Thrombin
2. Complex activates Protein C 3. Results in APC |
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What does APC do? What type of molecule is it?
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A protease - floats off, binds Protein S and inactivates Fx 8a and 5a -> destroys the enzymatic machines that make Thrombin.
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What do we call the action of Thrombomodulin?
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Natural anticoagulation
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When does Thrombomodulin and Protein C anticoagulation occur?
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Constantly
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What diseases affect the Thrombomodulin pathway?
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-Protein C deficiency
-Protein S deficiency |
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What results from ProteinC/S deficiency?
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Porphyra purpura fulminans - many small bruises on infants just after birth due to widespread activation of coagulation.
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What happens if you don't have the APC/Thrombomodulin pathway?
(term for it) |
The whole body clots itself to death - Thrombophilia
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What is the most common abnormality related to the Thrombomodulin/protein c pathway?
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Factor V Leiden
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What is Factor V Leiden?
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Mutation of Factor V so that it resists APC and is not cleaved by it.
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Result of FVLeiden:
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High risk of thrombosis
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How many people have the Factor V Leiden mutation?
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1/20
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Why is the Fx V Leiden mutation so prominent in the population?
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Because having it protects you from sepsis.
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Why does the FVLeiden mutation protect against sepsis?
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It binds bacteria if they get into blood and aggregates them, making the clump more susceptible to macrophages.
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Most common genetic trait that predisposes patients to thrombosis:
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Fx V Leiden
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How is a clot removed?
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Fibrinolysis
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What molecule achieves fibrinolysis?
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Plasmin
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What does Plasmin do to fibrin?
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Chops it up into little pieces called D-dimers
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D-dimer is an indication of:
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How active the fibrinolysis process is
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What is the fibrinolysis pathway similar to?
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Coagulation
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What is the most important inhibitor of fibrinolysis?
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PAI-1 -> plasminogen activator inhibitor
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5 Primary bleeding disorders:
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-Glanzmann's thrombasthenia
-Bernard Soulier -vWD -Hemophilia A -Hemophilia B |
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Glanzmann's Thrombasthenia
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GPIIBIIIa - fibrinogen receptor on platelets mutated
2,3,F,G |
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Bernard Soulier Syndrome
-symptom |
GPIb-a - vWF receptor on platelets defective
Symptom: giant platelets |
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von Willebrand disease
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problem with vWF - also will see problems with Fx VIII because it's the chaperone
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Hemophilia A
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Fx 8 deficiency
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Hemophilia B
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Fx 9 deficiency
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3 types of Secondary bleeding disorders
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-Vit K deficiency
-Liver disease -Thrombocytopenia |
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How are bleeding disorders treated?
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With replacement therapy of plasma or pure factors
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What type of tube do you collect blood for PT or PTT? Why?
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Citrate - to remove the calcium and prevent activation.
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What measures the common pathway?
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Protime
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What does the PTT measure?
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Intrinsic and Extrinsic factors
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What ingredients do you add for the PT?
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-Phospholipid
-Ca -Tissue factor (thromboplastin) |
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What ingredients do you add for the PTT?
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-Kaolin (surface)
-Phospholipid -Calcium |
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What is the TcT (Thrombin clotting time) used to test?
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How well your fibrinogen is functioning.
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What do you add to run the TT?
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-Lots of Thrombin
-Calcium |
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How are the PT and PTT expressed?
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INR - international normalized ratio
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3 Drug strategies for treating hemostasis problems:
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-Anticoagulants
-Antiplatelets -Fibrinolytics |
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3 types of anticoagulant drugs:
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-Coumadin
-Heparin -Hirudin |
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What does Coumadin do?
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Inhibits gamma-carboxylation of Vit-K dependent factors
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What does Heparin do?
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Enhances AT3 action (mimics heparansulphat proteoglycans)
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What is hirudin?
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Similar to AT3; inhibits the TAT complex.
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What is the #1 most common genetic cause of hypercoagulation?
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Fx V Leiden mutation - APC resistance
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What is the #2 most common cause of hypercoagulation?
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Increased Prothrombin levels
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What is more common, primary or secondary causes of hypercoagulation?
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Secondary
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Common types of secondary causes of hypercoagulative states:
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-Cancer
-Pregnancy -Diabetes mellitus -Sepsis -Stasis -Obesity |
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Why is pregnancy associated with hypercoagubility?
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Because as the body prepares for massive trauma and bleeding it ramps up its coagulative mechanisms.
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Why is sepsis associated with hypercoagubility?
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Because bacteria induce clotting
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Why is obesity associated with hypercoagubility?
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Because fat cells produce PAI-1 which is an inhibitor of plasmin so reduces the natural anticoagulative pathway.
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If a patient shows up with massive clotting and has no other symptoms or predisposing factors what would you suspect?
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Cancer
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Why is inflammation associated with hypercoagubility?
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Because it causes tissue factor to be expressed on endothelial cells, which otherwise do NOT express it normally.
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How is platelet function tested?
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By aggregation studies
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What agonist detects vWF function?
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Ristocetin
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4 agonists used to test platelet function:
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-ADP
-Epinephrine -Collagen -Ristocetin |
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3 Types of Antiplatelet drugs:
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1. Fibrinogen receptor blockers
2. Thromboxane synthesis inhibitors 3. ADP receptor blockers |
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What receptor is blocked when blocking the fibrinogen receptor? Example of one of these drugs:
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GPIIbIIIa
Example: RGD mimetics |
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What are 3 TxA2 synthesis inhibitors?
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-Cox inhibitors -> ASPIRIN or INDOMETHACIN
-Phospholipase inhibitors -> STEROIDS |
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What are 2 clotbusters?
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-TPA
-Streptokinase |
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What do TPA and Streptokinase do?
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Activate Plasminogen
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